Project Summary: The candidate is a mechanical engineer with extensive experience in the evaluation of blood vessel mechanical behavior, with a particular interest in the cerebral vasculature and its role in traumatic brain injury (TBI). His short-term goal is to supplement his quantitative background with a deeper understanding of the principles and methods of neuroscience and vascular biology and to learn advanced research methods in these areas. Through the training provided by this award, he hopes to develop an independent, interdisciplinary research program that can effectively explore the relationship between blood vessel mechanics and biology. The proposed training plan includes coursework focusing on fundamental principles and techniques of biology, practical instruction in experimental biology, and attendance at a variety of meetings and seminars ranging from the mentor and laboratory level to that of national conferences. The training portion of the proposal is coupled with a focused research plan designed to address the general hypothesis that matrix metalloproteinases (MMPs) are acutely activated in cerebral blood vessels as a result of mechanical loading, leading to degradation of vascular integrity. This hypothesis will be addressed by (1) defining the relationship between mechanical stretch and MMP activity in isolated normal cerebral blood vessels, (2) comparing MMP activity in vessels injured in vivo to findings in isolated vessels, and (3) correlating mechanical deformation, MMP activity, and vessel permeability in an in vivo injury model. The plan builds on the candidate's expertise in blood vessel mechanical testing and adds directions of inquiry that directly relate to the mentors'collective expertise in vascular biology and neuroscience. The effort will be undertaken at the University of California, San Francisco, one of the leading health science education and biomedical research centers in the world. Relevance: Traumatic brain injury (TBI) is a major cause of death and disability and is frequently associated with the failure of cerebral blood vessels. MMPs have been implicated in the pathophysiology of TBI, and evidence suggests increased activity of MMPs in response to vessel deformation. Characterization of the relationship between mechanical loading and injurious vascular biological response will provide important information for potential therapeutic interventions and will add to the state of knowledge on tolerance.